Does simultaneous soft tissue augmentation around immediate or delayed dental implant placement using sub-epithelial connective tissue graft provide better outcomes compared to other treatment options? A systematic review and meta-analysis

Objective The clinical benefits of simultaneous implant placement and soft tissue augmentation using different treatment modalities are unclear. The current meta-analysis aimed to compare the effect of simultaneous soft tissue augmentation using subepithelial connective tissue graft (SCTG) around immediate or delayed dental implant placement with other treatment modalities on the peri-implant tissue health and esthetic. Methods Up to May 2021, four databases (PubMed, EMBASE, Cochrane Central, and Google Scholar) were searched. Randomized control trials with follow-up >3 months, evaluating simultaneous implant placement (immediate or delayed) and soft tissue augmentation using SCTG compared with other treatment modalities were included. The predictor variables were SCTG versus no augmentation with/without guided bone regeneration (GBR) or other augmentation techniques (Acellular dermal matrix (ADM), Xenogeneic collagen matrix (XCM). The outcome variables were buccal tissue thickness (BTT), mid-buccal gingival level (MGL), marginal bone loss (MBL), and pink esthetic scores (PES). Cumulative mean differences (MD) and 95% confidence interval (CI) were estimated. Results Twelve studies were included. SCTG along with immediate implant placement (IIP) or delayed implant placement (DIP) showed a statistically significant improvement in BTT (Fixed; MD, 0.74; 95% CI, 0.51; 0.97), MGL (Fixed; MD, 0.5; 95% CI, 0.21; 0.80), PES (Fixed; MD, 0.79; 95% CI, 0.29; 1.29), and less MBL (Fixed; MD, -0.11; 95% CI, -0.14; -0.08) compared to no graft (P<0.05). A statistically insignificant differences in BTT (Random; MD, 0.62; 95% CI, -0.41; 1.65), MGL (Fixed; MD, -0.06; 95% CI, -0.23; 0.11), MBL (Fixed; MD, 0.36; 95% CI, -0.05; 0.77) and PES (Fixed; MD, 0.28; 95% CI, -0.10; 0.67) was observed when SCTG along with DIP was compared with no augmentation plus GBR. Similarly, no statistically significant difference was observed when comparing SCTG along with DIP with acellular dermal matrix (ADM) concerning BTT (MD:0.71, P = 0.18) and KMW (MD: 0.6, P = 0.19). Conclusion There is a very low quality of evidence to provide recommendations on whether simultaneous dental implant placement (IIP or DIP) and soft tissue augmentation using SCTG is superior to no augmentation or is comparable to the other tissue augmentation materials in improving the quality and quantity of peri-implant tissues. Therefore, further, well-designed RCTs with larger sample sizes and long follow-up times are still needed.


Introduction
Dental implants are widely used for the replacement of missing teeth. Recently, osseointegration around dental implants comes to be a foreseeable procedure; therefore, the focus has been shifted from obtaining osseointegration to achieve a satisfying aesthetic appearance [1,2]. Providing a naturally looking peri-implant tissue, particularly in the esthetic zone, is a complex and challenging undertaking for the dental implant team. Adequate buccolingual and apicocoronal dimensions of hard and soft tissues are essential for optimal function and esthetic after dental implantation [3,4]. Sometimes the placement of the dental implant in the esthetic zone either into healed bone or into the extraction socket is associated with esthetic problems especially for patients who show their maxillary gingival scallop while smiling or talking [5]. Esthetics complications are usually caused by a lack of sufficient bone after tooth loss. Management of bone deficiency prior to or at the time of dental implant placement using several bone augmentation techniques has been summarized in Cochrane Systemic reviews [6,7]. However, there are situations in which it might be possible to solve the unpleasant esthetic results solely through manipulating or augmenting soft tissues [8]. Soft tissue augmentation can be carried out at different time points during implant treatment either simultaneously, during the phase of tissue integration or it can be delayed after final implant loading [2]. Simultaneous soft tissue augmentation at the time of dental implant placement using subepithelial connective tissue graft (SCTG) [9] or other substitutes such as xenogenic collagen matrix (XCM) [10,11], acellular dermal matrix (ADM) [12] has been recommended to reduce crestal bone loss in a patient with thin gingival biotype [13,14], to prevent mid-facial mucosal recession [14,15], to avoid shimmering through implant parts, especially those made of titanium [16].
SCTG harvested from the hard palate or tuberosity region has become the gold standard technique to thicken peri-implant tissue and to improve esthetic. However, SCTG has been criticized to be associated with donor site morbidity and long operative time. To overcome such downsides, XCM and ADM have been used as an alternative to the SCTG for soft tissue augmentation around the dental implant. Recently, a considerable number of systemic reviews and meta-analyses concerned with the effectiveness of soft tissue augmentation in the healthy and diseased soft tissue around dental implant, [17] timing of graft placement [2], the changes of keratinized thickness [18], and the effect of augmentation on the esthetic outcomes around dental implant [19] or evaluate success rate, and complications associated between type 1 and other types of implant placement protocols [20] have been published. Lin et al [2] showed that no difference between simultaneous and staged soft tissue augmentation during implant treatment. Thoma et al [17] concluded that soft tissue grafting procedures result in more favorable peri-implant KMW, BTT, and MBL, compared to no grafting protocol. In another systematic review, Esposito et al [8] concluded that there is insufficient reliable evidence to provide recommendations on whether techniques to correct/augment peri implant soft tissues or to increase the width of keratinized/attached mucosa are beneficial to patients or not.
Recently, Stefan, et al conducted a systematic review and they reported that soft tissue augmentation is beneficial regarding width of keratinized mucosa and midfacial recession and showed no influence regarding peri implant MBL [21]. Similarly, Angelis et al found that SCTG improve peri implant soft tissue thickness and alleviate soft tissue recession and marginal bone loss when placed simultaneously with IIP protocol [22]. However, there is a lack of clear evidence regarding the clinical and aesthetic benefits of simultaneous soft tissue augmentation around immediate or delayed dental implant placement using SCTG compared with no grafting (with or without GBR) or with different augmentation procedures (CM and ADM). Therefore, this study was conducted to systemically review and critically evaluate studies that compared soft tissue changes after various augmentation techniques at the dental implant site and to answer the question "Does simultaneous soft tissue augmentation around immediate or delayed dental implant placement using SCTG provide better outcomes compared to other treatment options?".
Changes in the buccal soft tissue thickness buccal (BTT), mid-buccal gingival level (MGL), marginal bone loss (MBL), keratinized tissue width (KMW), and Pink esthetic score (PES) were considered as the predictors of comparisons between different surgical procedures.

Materials and methods
In this systematic review and meta-analyses, the authors follow the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement (S1 Checklist) [23]. The protocol of this meta-analysis has been registered in PROSPERO (registration number CRD42019123118).

Focused question
Does simultaneous soft tissue augmentation at the time of immediate or delayed implant placement using subepithelial connective tissue graft provide better outcomes compared to other treatment options?
The question for the current meta-analysis was adopted to follow PICO criteria: P: Adult healthy partially edentulous patients received single dental implant placement in the extraction socket or healed site.
I: Soft tissue augmentation using SCTG (harvested from the palate or maxillary tuberosity) or other augmentation materials (ADM, or XCM) around immediate or delayed dental implant placement.

T:
The patients in all included studies should be followed for more than 3 months after simultaneous implant placement and soft tissue augmentation.

S: Randomized controlled trials (RCTs) (split-mouth and parallel studies).
Change in MGL is defined as apical migration of the gingival margin toward the platform of the dental implant. BTT is measured 1 to 2 mm below the implant gingival margin and classified as thin gingival biotype (if � 1 mm) or thick gingival biotype (if > 1 mm). MBL is defined as the distance from the implant-abutment interface on the implant side to the marginal bone. KMW is defined as the distance between the gingival margin and the mucogingival junction.

Search strategy
From inception to May 2021, An electronic search of PubMed, EMBASE, and Cochrane Central, Google Scholar was performed by two reviewers independently (S1 File). Incorporation of the following keywords were used for the electronic search in PubMed: (

Inclusion/exclusion criteria
Qualified studies that fulfill the following criteria were included: 1) English-language human randomized controlled trials (RCTs), 2) Single dental implant placed in the extraction socket or healed site with simultaneous soft tissue augmentation 3) RCTs with follow-up >3months. 4) RCTs that compared SCTG with other augmentation techniques. 5) RCTs that reported at least one of the following variables: BTT, KMW, MGL, MBL, or PES.
Studies that reported one of the following criteria were excluded: 1) not RCT and no simultaneous soft tissue augmentation was performed at the time of dental implant placement. 2) Sample size less than 10 patients, 3) review studies, meeting abstracts, case reports, case series, and non-English articles. 3) Studies < 3month follow-up period.

Data extraction process
Two researchers (TA., GQ.) independently assessed the titles, abstracts, and full-text of the relevant studies. All of the following data in the included studies were collected when available: study design, number of patients, publication year, age range, mean age, implant number, company, type of intervention, flap or flapless, hard tissue augmentation, follow-up period, and outcome variables (Table 1). Two researchers (A. TA. DLL.) collected the data regarding outcomes of interest, any disagreements between the reviewers were resolved by consensus.

Risk of bias assessment
Two authors (A. TA., MA. M) independently assessed the risk of bias in the included studies. Quality assessment of the risk of bias for all included studies was carried out using Cochrane collaboration's tool. All studies were evaluated using the RCT checklist that involves random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selected reporting, and other biases. If all criteria were met, the study rated as a low risk of bias. If one or more key domains were unclear, the study considered an unclear risk of bias. Studies that did not meet one or more of these criteria were classified as having a high risk of bias. In case of disagreement, the consensus was reached by consultation with a third reviewer was performed (WLP.).

Certainty of the evidence
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach of the meta-analysis was utilized to identify the certainty of effect estimates from the meta-analysis for all outcomes of interest. In the GRADE system, RCTs are rated as high-quality evidence but they may be downgraded due to limitations in one or more of the following domains: risk of bias, inconsistency, indirectness of evidence, imprecision, and publication bias [24]. The summary of confidence for the present evidence was estimated using RevMan [25].

Statistical analysis
The analysis was conducted to compare the effect of simultaneous soft tissue augmentation of different techniques on peri-implant tissue. All collected data in the current review were continuous data, and the weighted mean differences (MD) and 95% confidence interval (CI) were used to construct forest plots of selected studies. The heterogeneity across studies was assessed by the Cochrane Q test (χ 2 test) and the I-squared index (I 2 ). I 2 = 0% to 25%, no heterogeneity; I 2 = 25% to 50%, moderate heterogeneity; I 2 = 50% to 75%, high heterogeneity; I 2 = 75% to 100%, extreme heterogeneity [26]. When I 2 < 50%, we used the random effect model described by DerSimonian and Laird [27]. Otherwise, the data was regarded as homogeneous, and a fixed-effect model was used. The p-value of <0.05 was considered statistically significant. A Sub-group meta-analysis was conducted to evaluate the effect of different Variables on the outcomes of interest. The Cochrane Collaboration's Review Manager Software (RevMan version 5.0) was utilized for data analysis.

Sensitivity analysis
Sensitivity analysis was performed to assess whether each individual study influenced the final results. This was performed by omitting one study at a time and calculating the pooled mean differences (MD) for the remaining studies.

Results
The electronic and manual searches identified 813 articles. Seven hundred thirty-two records remained after duplicates were removed. The titles and abstracts of the remaining 732 articles were screened, and 712 were excluded due to being topic-off or non-English studies. Two researchers carefully read the full text of the remaining 20 studies for potential inclusion.    Finally, 12 RCTs studies [5,[28][29][30][31][32][33][34][35][36][37][38] met the inclusion criteria and were included in our metaanalysis (Fig 1) ( Table 1). The other 8 articles were excluded for reasons ( Table 2). The followup ranged from four to 24 months. The minimum follow-up was reported to be 4 months in one study [30], whereas the maximum follow-up was reported to be 24 months [36] (Table 1).

Quality assessment of the included studies
The full checklist (Cochrane Collaboration's tool for assessing the risk of bias) was applied for the assessment of the included RCTs. Two trials [5,31] were considered as a low risk of bias, Five articles [28, 30, 32, 33, 37] were rated as unclear risk, and five studies were rated as high risk of bias [29, 34-36, 38] (Fig 2).

Confidence of evidence
Based on the results of the GRADE assessment tools (S2 File), the quality of evidence for all analysis was rated as having a very low quality of evidence. The quality of evidence was downgraded because of limitations in the study design (risk of bias) and imprecision.  • Pink aesthetic score was reported in three studies with 124 participants [29, 36, 37] along with IIP. SCTG showed a statistically significant improvement in the pink aesthetic score compared to no graft (Fixed; MD, 0.79; 95% CI, 0.29, 1.29, P = 0.002) (Fig 6).

Author(s)/ year Title Reason
Lorenzo et al, 2011 [39] Clinical efficacy of a xenogeneic collagen matrix in augmenting keratinized mucosa around implants: a randomized controlled prospective clinical trial.

Soft tissue augmentation was performed to treat gingival recession around an osseointegrated dental implant
Rungcharassaeng et al. 2012 [40] Immediate implant placement and provisionalization with and without a connective tissue graft: an analysis of facial gingival tissue thickness No randomization was reported Bianchi and Sanfilippo, 2004 [41] Single-tooth replacement by immediate implant and connective tissue graft: a 1-9-year clinical evaluation.

Data reported in percentage
Zafiropoulos and John 2017 [42] Use

Soft tissue augmentation along with DIP. A-SCTG versus no graft plus DIP.
• One study (n = 60) [33] with 1-year follow-up compared two types of soft tissue augmentation (SCTG and XCM) with no graft along with DIP in the preserved socket. After 12

B-SCTG versus No soft tissue grafting plus GBR with DIP.
Three articles with a total sample size of n = 74 patients compared SCTG with no augmentation plus GBR [28, 31, 32]. Two studies of the same trial and same participants but with different outcomes were conducted by De Bruyckere et al [28,32]. The three studies were included in the evaluation of the following outcomes: Two studies [28, 31] compared SCTG with no augmentation plus GBR in regarding MGL and BTT, and a statistically insignificant difference was observed (Fixed; MD, -0.06; 95% CI, -0.23-0.11, P = 0.47) (Random; MD, 0.62; 95% CI, -0.41-1.65, P = 0.24) (Fig 7A and 7B). Also, no statistically significant difference was observed regarding MBL and KMW then comparing SCTG with no augmentation plus GBR (Fig 8).

C. SCTG versus other augmentation techniques (CM or ADM) plus DIP.
• Two studies compared SCTG with ADM along with DIP, a total of 20 patients with 4 months follow-up were included in the study performed by Hutton et al [30]. Four months postoperatively, no statistically significant differences in terms of BTT (MD:0.71, P = 0.18) and KMW (MD: 0.6, P = 0.19) were observed between ADM and SCTG. Another study compared SCTG with ADM with a total of 24 patients and 12 months follow-up [34] and showed a

Discussion
Based on the results of the GRADE assessment, there is a very low quality of evidence showing that simultaneous soft tissue augmentation around immediate or delayed dental implant placement results in an improvement in the quality and the quality of the peri-implant tissue. The present study showed that soft tissue augmentation is a beneficial procedure to prevent a midfacial recession, increase BTT, and reduce MBL, and this was regardless of the timing of implant placement protocol used. SCTG was compared with no augmentation in conjunction  [40,48], and this surgical option can be considered in cases with non-salvageable teeth showing gingival recession, in cases of absence of attached gingiva, and to conceal underlying implant restorative materials [37,46,49]. The result obtained from the present systemic review and meta-analysis support that soft tissue augmentation using SCTG significantly improve BTT around dental implant regardless of whether immediate or delayed placement protocol was employed. The gains in BTT after one year of follow-up were 0.84 mm in the studies that performed simultaneous SCTG augmentation along with IIP and 1.3 mm in the study performed SCTG along with DIP. However, these results should be interpreted with caution because of high heterogeneity among studies that evaluated SCTG along with IIP, and only a single study evaluated SCTG along with DIP.
One important factor that has been considered as a prognostic factor for the esthetic outcome is the gingival biotype [50,51]. It has been reported that gingival thickness at the crest plays a crucial role in marginal bone stability around the implant. Further, it has been reported that less mid-buccal recession occurs in the thick gingival biotype group compared with the thin group [52]. Kan et al demonstrated that sites with a thick gingival biotype exhibited significantly smaller changes in facial gingival level than sites with a thin gingival biotype [53]. Farina and Zaffe [54] concluded that soft tissue augmentation under thin gingival biotype using ADM increases gingival thickness more than that in the thick gingival biotype, whereas a decrement was found in control sites with no graft used. Our finding is consistent with the study conducted by Speroni et al [55] in that the thick gingival biotype along with SCTG showed a statistically significant increase in BTT of about 0.8 mm compared with thin gingival  biotype which showed a statistically insignificant change of about 0.3 mm. However, this result was obtained from a single study with a very low quality of evidence [36].
A subgroup meta-analysis of the change in the mucosal thickness after one and two years showed a mean difference of about 0.84 mm and 0.60 mm respectively when SCTG compared with no graft along with IIP. The mean loss of the BTT between 1year and 2 years was minimal about 0.24 mm. This was in line with the study conducted by Sanz-Martín et al [56] who reported a mean reduction of about 0.3 mm in the buccal tissue contours between 6 months and 1 year. Interestingly, some studies reported a considerable increase in the soft tissue thickness after immediate implantation placement even if no soft tissue augmentation was used [40,57].
GBR could also be considered to play a role in increasing the stability of peri-implant soft tissue and preventing marginal tissue shrinkage. It has been reported that marginal gingival change may occur after immediate implant placement particularly in the esthetic zone [58]. Therefore, it has been suggested to fill the gap between the implant and buccal bone plate with a bone graft to reduces bone resorption [59]. Unfortunately, no study in the current meta-analysis tested the effect of SCTG versus GBR along with IIP. Instead, two trials that compared the effect of simultaneous soft tissue augmentation using SCTG with GBR [28, 31] along with delayed implant placement were included. Surprisingly, the results seem that GBR produced a comparable effect to the SCTG in improving BTT, MGL, and PES P = 0.24, 0.47, and 0.14 respectively.
Comparing SCTG versus XCM or ADM along with DIP showed a comparable effect in improving the quality and quantity of the peri-implant tissue. Lorenzo et al. [39] reported that no statistical difference was observed between SCTG and XCM regarding the buccal recession (P = 0.667) and this was in line with our findings. Huber et al. [60] and Thoma et al. [17] showed no statistically significant difference in buccal tissue thickness when SCTG compared with XCM. Alternatively, Cairo et al. [43] showed that a significant increase in BTT in the SCTG group when compared with the XCM group. However, these studies [43,60] were excluded from the current review because soft tissue augmentation was not performed simultaneously at the time of implant placement ( Table 2). Comparing SCTG with ADM concerning MGL, BTT, MBL, and PES showed no statistically significant difference P>0.05. This finding was in line with the studies conducted by Liu et al. [61] which was excluded from the current meta-analysis because the article was written in the Chinese language. Also, this result was in line with the studies that compared the effect of SCTG with ADM in the treatment of gingival recession around natural teeth [62,63].
We notice several limitations in the current meta-analysis that should be declared. First, most of the included studies were assessed as having a high risk of bias. Second, only RCTs were assessed which result in a limitation in the number of included studies; therefore, considering the inclusion of both RCT and non-RCT studies in the future meta-analysis would be beneficial to ensure that all relevant information will be tested. Third, the small sample size in the included studies. Fourth, high heterogeneity in some analyses due to the difference in study design, recruitment of the participants, and methods used for the assessment of outcomes. Fifth, the non-English studies in the current review were excluded. Finally, several cofounders that may affect on the outcomes of interest were not evaluated by most of the included studies, such as follow-up time, site of SCTG harvest (from the palate or maxillary tuberosity), gingival biotype, implant diameter, implant system, implant surface, implant design, type of abutment used, using bone graft or not, and whether immediate provisionalization was used or not. However; for an optimum comparison of different peri-implant tissue augmentation surgeries with the least bias, homogeneous sample of participants with the same implant placement techniques (IIP and DIP), implant insertion site, augmentation techniques (soft and/or hard augmentation), follow up times (>3 months follow-up period) is recommended. All the aforementioned limitations preventing us from drawing a defective conclusion regarding the effect of simultaneous soft tissue augmentation around immediate or delayed dental implant placement on the peri-implant health and aesthetic. Therefore, the results of the current meta-analysis should be interpreted with caution, and further RCTs with a large sample size, longer follow-up period, and clearer design that compares the SCTG and no graft or other soft tissue substitutes are required.

Conclusion
Within the limitations of the current meta-analysis, it seems that: 1. Simultaneous soft tissue augmentation using SCTG at the time of immediate implant placement improves BTT and PES, prevents mid-buccal recession, and reduced MBL compared with NG.
2. SCTG compared with GBR along with DIP showed a statistically insignificant difference concerning MGL, BTT, and PES.
3. ADM and CM in conjunction with DIP produce a comparable effect to SCTG in improving periimplant quality and quantity.
However, this conclusion should be interpreted with caution due to the very low quality of evidence for all analyses. Therefore, further, well-designed RCTs with larger sample sizes and long follow-up times are still needed. 17. Thoma